Triptan drugs

Triptans are a group of synthetic serotonin receptor agonists that are used in the therapy of migraine and vascular headaches. Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine that has multiple actions, acting as a neurotransmitter and bioactive amine. The triptans are serotonin agonists with high affinity for the 5-HT_1B and 5-HT_1D receptors which are found on smooth-muscle cells of blood vessels. Simulation of the 5-HT_1D receptor results in constriction of intracranial blood vessels. The triptans may also block the release of vasoactive peptides from perivascular trigeminal neurons through their action at presynaptic 5-HT_1D receptors on nerve terminals. Regardless, the triptans have been found to be effective in preventing or aborting migraine headaches with shortening of the period of pain and symptoms. The triptans are considered “first line” agents for patients whose vascular headaches do not reliably respond to conventional analgesics. Triptans generally have a more rapid onset of action and fewer side effects than the ergot alkaloids. Triptans may be taken subcutaneously, orally as tablets, capsules, or quick-dissolving wafers, or intranasally as a spray.

Currently, seven triptans are approved for use in the United States including almotriptan, eletriptan, forvatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan, as well as a fixed-dose combination product containing sumatriptan plus naproxen. Generic formulations are available for most agents. The short acting triptans include sumatriptan, almotriptan, eletriptan, rizatriptan and rolmitriptan and generally provide relief within 30 to 60 minutes. The longer activing oral triptans include naratriptan and frovatriptan which have a slower onset of action but may be better tolerated. Intranasal formulations may have a more rapid onset of action as do subcutaneous administered forms. Brand names, year approved, tablet or wafer size, usual dose and maximum daily recommended doses are shown in the Table 1.

Comparing the clinical efficacy and harms of the different triptans has been an area of considerable interest to researchers and patients, but is complex because of the large variety of outcome measures that can be measured in studies ¹.

Early therapy is recommended in patients with recurrent migraine, and typically the dose is repeated in 2 to 4 hours if relief has not occurred. However, the total dosage should be limited to 2 to 3 doses per 24 hour period. Parenteral and intranasal administration is helpful in patients with nausea and vomiting. Chronic, long term use of triptans to prevent migraines has been studied, but is not currently approved. The seven triptans have similar side effect profiles which include “triptan sensations” characterized by tightening of the throat, chest, neck and limbs with paresthesias and hot or cold sensations. Triptans may also cause flushing, headache, somnolence and fatigue. Rare but potentially severe adverse events include medication overuse syndrome, cerebrovascular and cardiovascular events such as myocardial infarction and stroke, serotonin syndrome and anaphylaxis.

Table 1. Triptan medications

Generic (Brand) Name	Year Approved	Tablet (or Wafer) Size	Usual Initial Dose	Maximum 24 Hour Dose
Almotriptan (Axert)	2001	6.25 and 12.5 mg	12.5 mg	25 mg
Eletriptan (Relpax)	2002	20 and 40 mg	40 mg	80 mg
Frovatriptan (Frova)	2001	2.5 mg	2.5 mg	7.5 mg
Naratriptan (Amerge)	1998	1 and 2.5 mg	2.5 mg	5 mg
Rizatriptan (Maxalt)	1998	5 and 10 mg	10 mg	30 mg
Sumatriptan (Imitrex)	1997	25, 50 and 100 mg*	50 mg	200 mg
Zolmitriptan (Zomig)	1997	2.5 mg and 5 mg**	5 mg	10 mg

Footnotes:

* Also available as nasal spray, transdermal patch and solution for injection.
** Also available in orally disintegrating tablets and as nasal spray.

Triptan mechanism of action

Triptans work by binding to serotonin receptors in the brain, which leads to a reversal of blood vessel swelling. The triptans are serotonin agonists with high affinity for the 5-HT_1B and 5-HT_1D receptors which are found on smooth-muscle cells of blood vessels. Simulation of the 5-HT1D receptor results in constriction of intracranial blood vessels. The triptans may also block the release of vasoactive peptides from perivascular trigeminal neurons through their action at presynaptic 5-HT_1D receptors on nerve terminals.

Best triptan for migraine

There is no consistent evidence that one triptan has any particular advantage or disadvantage over another in any subgroup based on age, race, gender, prophylactic treatment, or menstruation-associated migraine ¹.

All triptans can help relieve migraines. Studies on the most commonly prescribed triptan, sumatriptan (50 mg), for example, show the following:

• Without sumatriptan, migraine pain went away within two hours in about 10 out of 100 people.
• With sumatriptan, the pain disappeared in the same time in 20 to 30 out of 100 people.

So an additional 10 to 20 out of 100 people had no pain two hours later. And the drug offered at least some pain relief in another 25 out of 100 people.

How quickly and effectively a drug works will also depend on the severity of the migraine, the dose of the drug and how it is administered. For instance, injections are faster and more effective than other forms of administration, but they also have more side effects.

Table 2. Triptan comparison summary of evidence

	Comparison: Overall strength of evidence	Conclusion
Key Question 1. Comparative effectiveness
a. Monotherapy vs. monotherapy	Eletriptan vs. other triptans: Fair	Evidence from 5 head-to-head trials insufficient for conclusions about comparative efficacy of eletriptan, encapsulated sumatriptan, naratriptan, and zolmitriptan due to the differential effects associated with use of unilateral encapsulation in these trials Fair evidence from 3 placebo- controlled trials suggests that eletriptan is at least equivalent in efficacy to the conventional tablet form of sumatriptan 100 mg
	Rizatriptan 10 mg vs. the conventional tablet form of sumatriptan 50 mg or 100 mg: Fair	Rizatriptan 10 mg at least comparable to the conventional tablet form of sumatriptan 50 mg and 100 mg in rates of 2-hour and 24- hours pain-free and 24-hour quality- of-life Superiority of rizatriptan 10 mg on 2- hour pain-free is possible but unclear due to mixed findings across trials
	Rizatriptan 10 mg vs. naratriptan 2.5 mg: Fair	Rizatriptan 10 mg superior to naratriptan 2.5 mg at 2 hours in rates of pain-free, presence of normal function, and satisfaction and comparable at 24 hours in recurrence and quality of life
	Rizatriptan 10 vs. zolmitriptan 2.5 mg: Fair	Rizatriptan 10 mg superior to zolmitriptan 2.5 mg at 2 hours in rates of pain-free and presence of normal functioning and comparable on 24-hour recurrence and quality of life
	Rizatriptan orally disintegrating tablets 10 mg vs. the conventional tablet form of sumatriptan 50 mg: Fair	Rizatriptan orally disintegrating tablet 10 mg superior on preference and 2- houroutcomes of pain-free and normal function and comparable on 24-hour outcomes in 2 open trials
	Rizatriptan orally disintegrating tablets 10 mg vs. eletriptan 40 mg	Comparable on satisfaction, pain-free, and functional disability Patient preference favors rizatriptan orally disintegrating tablet 10 mg
	Zolmitriptan 5 mg vs. the conventional tablet form of sumatriptan 100 mg and 50 mg: Fair	Comparable efficacy in pain outcomes Zolmitriptan 5 mg and the conventional tablet form of sumatriptan 50 mg were consistently comparable across 6 headaches
	Zolmitriptan 2.5 mg vs. naratriptan 2.5 mg: Poor	Comparable in adjusted rates of 2- hour pain-relief Unadjusted outcomes cannot be meaningfully interpreted.
	Zolmitriptan 2.5 mg and 5 mg nasal spray vs. zolmitriptan 2.5 mg oral tablet: Fair	Zolmitriptan 5 mg nasal spray superior to zolmitriptan 2.5 mg oral tablet in pain-free at 30 and 45 minutes and in normal function at all time points and comparable for later outcomes Zolmitriptan 2.5 mg had no advantage over zolmitriptan 2.5 oral tablet at early times and was inferior on later outcomes
	Almotriptan 12.5 mg vs. other triptans: Fair	Almotriptan 12.5 mg similar to the conventional tablet form of sumatriptan 50 mg and 100 mg and zolmitriptan 2.5 mg on 2-hour pain- free, 24-hour recurrence, and 24- hour pain-free Almotriptan 12.5 mg compared with rizatriptan 10 mg: Patient preference was almost identical, but 2-hour pain-free rates were superior for rizatriptan
	Naratriptan 2.5 vs. mg the conventional tablet form of sumatriptan 100 mg: Fair	Similar for 2-hour and 24-hour sustained pain relief Pain-free outcomes not reported
	Reformulated sumatriptan (rapid-release): Poor	No head-to-head trials Indirect comparisons from placebo- controlled trials suggests that reformulated sumatriptan is at least similar in efficacy to the conventional tablet form of sumatriptan 100 mg
	Sumatriptan nasal spray and injection: Poor	Head-to-head trials comparing subcutaneous sumatriptan with other triptans were poor quality No head-to-head trials were found for sumatriptan nasal spray
	Frovatriptan: Poor	No fully published head-to-head trials 5 placebo-controlled trials (N=2866) suggest frovatriptan is probably inferior to the conventional tablet form of sumatriptan 100 mg
b. Fixed-dose combination tablet vs. monotherapy	Treximet® (reformulated sumatriptan 85 mg/naproxen 500 mg) vs. reformulated sumatriptan 85 mg: Good	Treximet ® superior in pain-free at 2 hours and 24 hours and in normal function, overall productivity, and patient satisfaction
c. Fixed-dose combination tablet vs. co-administration of individual components	Treximet® (reformulated sumatriptan 85 mg/naproxen 500 mg) vs. co-administration of individual components: Poor	No trials found
Key Question 2: Comparative safety
a. Monotherapy vs. monotherapy	Almotriptan, eletriptan, naratriptan, rizatriptan oral tablet, rizatriptan orally disintegrating tablet, the conventional tablet form of sumatriptan, zolmitriptan oral tablet, zolmitriptan orally disintegrating tablet, zolmitriptan nasal spray: Good	Comparable overall tolerability and no consistent differences in chest pain/tightness or central nervous system effects
	Frovatriptan, reformulated sumatriptan, the conventional tablet form of sumatriptan injection and nasal spray: Poor	None or poor-quality head-to-head trials
b. Fixed-dose combination tablet vs. triptan monotherapy	Treximet® (reformulated sumatriptan 85 mg/naproxen 500 mg) vs. reformulated sumatriptan 85 mg: Good	No consistent difference in rates of overall adverse events, dizziness, paresthesia, or somnolence
c. Fixed-dose combination tablet vs. co-administration of individual components	Treximet® (reformulated sumatriptan 85 mg/naproxen 500 mg) vs. co-administration of individual components: Poor	No head-to-head trials
Key Question 3: Subgroups
	All triptans: Poor	No evidence that any one triptan has a particular advantage or disadvantage over others in any subgroups based on age, gender, race, use of prophylactic treatment, or association with menstruation

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Triptan side effects

The possible side effects of triptans include drowsiness, unusual sensations such as tingling, weakness, heat or cold, and sometimes mild nausea as well. Using a suppository or injection might help avoid nausea. But triptans aren’t suitable for people who have cardiovascular (heart and blood vessel) diseases. This is because triptans can narrow the blood vessels and increase blood pressure, although this is rare.

Sumatriptan can cause adverse central nervous system events outside migraine attacks. It can cause mild sedative effects such as sleepiness or fatigue. It also causes a significant increase in the EEG alpha power as compared with the placebo. In a study measured by the Yale-Brown Scale, sumatriptan worsened the symptoms of patients with obsessive-compulsive disorder (OCD). Sumatriptan also can cause a transient rise in blood pressure, but the rise of blood pressure is the same as would be anticipated during moderate exercise. Subcutaneous injection administered by the physician results in transient stinging at the site of injection in most subjects; however, toleration is better when the subjects use the auto-injector. Sumatriptan can induce angle-closure glaucoma, but this is a rare event and should be treated correctly and promptly to prevent visual loss. A common adverse drug reaction of subcutaneous sumatriptan includes injection site reaction (bleeding, bruising, erythema). Intranasal sumatriptan leads to dysgeusia and nasal discomfort. Sumatriptan works earlier and more completely as compared to a combination of caffeine and ergotamine, but sumatriptan is associated with a higher rate of recurrent headaches. Rothner et al. reported a case of facial nerve palsy in a teenager using sumatriptan nasal spray. Hossein et al. described a recurrent paresis of the superior division of the oculomotor nerve occurring after subcutaneous administration of the drug. A thorough evaluation should be done of the patients who present with acute onset of a severe headache, and sumatriptan should be administered carefully since it could precipitate RCVS (Reversible cerebral vasoconstriction syndrome) or aggravate cerebral vasoconstriction. Vascular imaging should be performed after several days if sumatriptan-induced reversible vasoconstriction syndrome is suspected.

References

1. Helfand M, Peterson K. Drug Class Review: Triptans: Final Report Update 4 [Internet]. Portland (OR): Oregon Health & Science University; 2009 Jun. Results. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47285
2. Helfand M, Peterson K. Drug Class Review: Triptans: Final Report Update 4 [Internet]. Portland (OR): Oregon Health & Science University; 2009 Jun. Summary. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47288